Coating and layering processes allow adding API and excipients onto carrier systems such as starter beads. Several goals can be satisfied, such as modified drug release, taste-masking, color, and more.
Characterization of layered pellets forms the basis of advanced pharmaceutical pellet design. These pellets consist of inert cores coated with active drug layers. Their detailed analysis ensures uniformity, strength, and consistent drug release. Layered systems offer precise dosing, extended or modified release, and taste masking. When the solid-state properties of the drug are modified through amorphization, the pellets can show faster dissolution and better bioavailability. In this study, researchers examined how a high-shear granulator can produce pellets that combine amorphized amlodipine besylate and hydrochlorothiazide, focusing on structure, performance, and stability.
Amlodipine besylate normally appears in a crystalline form with high solubility and a melting point near 200 °C. In contrast, hydrochlorothiazide is poorly soluble and melts near 270 °C. Turning them into an amorphous or co-amorphous form breaks down the crystal lattice, improving solubility and dissolution rate. In co-amorphous systems, the two drugs interact through hydrogen bonding, which stabilizes the amorphous state and prevents recrystallization. This interaction increases the dissolution of both drugs and enhances their bioavailability. The study found that partially amorphized drug mixtures in layered pellets improved release rates while maintaining physical stability.
A high-shear granulator creates these layered systems efficiently. Its strong mechanical forces and controlled heat allow uniform coating and induce amorphization at the same time. Because it works without solvents, this process is clean, fast, and suitable for sensitive compounds.
Summary of the Publication
In the study The Development and Characterization of Layered Pellets Containing a Combination of Amorphized Amlodipine Besylate and Hydrochlorothiazide Using a High-Shear Granulator, Mahmoud et al. [1] developed layered pellets by coating microcrystalline cellulose cores (CELLETS®) with drug mixtures in different molar ratios (2:1, 1:1, 1:2). The high-shear granulator (ProCepT 4M8) operated at 1,500 rpm and 60 °C for three hours. The goal was to achieve partial amorphization and study its impact on dissolution and stability. After preparation, the pellets were stored at –20 °C before testing.
Differential scanning calorimetry showed that amlodipine lost its sharp melting peak, confirming full amorphization. Hydrochlorothiazide retained a broad, weaker peak, meaning it was only partly amorphous. X-ray diffraction supported this: the 2:1 mixture had the lowest crystallinity (26.8 %), while the 1:2 mixture showed the highest (53.6 %). Micro-CT imaging revealed that the drug formed an even layer around the CELLETS® cores. Although some pores appeared, they were inherent to the cores rather than defects from coating.
Texture analysis indicated a small increase in hardness—from 19.8 N for plain CELLETS® to around 21 N for layered pellets—showing the coating slightly strengthened the structure. Dissolution testing showed moderate improvement for amlodipine and a strong improvement for hydrochlorothiazide, with release rates increasing up to 2.6 times. The faster release resulted from reduced crystallinity, improved wettability, and closer contact between drug and medium. FTIR spectra revealed broadening and merging of N–H peaks, confirming new hydrogen bonding and lattice disruption. Stability testing over one month showed that 2:1 and 1:1 ratios stayed mostly amorphous, while the 1:2 mixture recrystallized heavily.
Use of CELLETS® in This Study
The authors used CELLETS®, spherical microcrystalline cellulose cores about 1 mm in size, as the foundation for layering. Their smooth and strong surfaces ensured even coating under high shear. Micro-CT confirmed complete drug coverage and consistent thickness. Moreover, the CELLETS® provided the mechanical strength needed to prevent pellet fracture during processing. Their stable core structure helped maintain uniform shape and resistance to deformation.
Conclusion and Outlook
The study proves that solvent-free high-shear granulation can produce layered pellets with amorphized drug mixtures. The characterization of layered pellets showed lower crystallinity, faster release, and stable structure. Using CELLETS® as cores provided excellent mechanical support. The co-amorphous state of amlodipine and hydrochlorothiazide improved dissolution, especially for the poorly soluble hydrochlorothiazide.
Looking ahead, future research should test long-term stability under stress and evaluate in vivo bioavailability. Scaling the high-shear process could make it viable for industrial use. Furthermore, exploring multi-layer systems or combining more drugs could expand the possibilities of characterization of layered pellets in modern pharmaceutical development.
https://cellets.com/wp-content/uploads/2025/10/Characterization-of-Layered-Pellets-containing-amorphized-amlodipine-besylate-and-hydrochlorothiazide.jpeg10131528Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2025-10-13 13:39:452025-10-13 13:39:45Characterization of Layered Pellets and the Role of Amorphized Amlodipine Besylate / Hydrochlorothiazide
Research Advances in MCC Pellet Technology and Applications
Scientific literature on MCC pellets highlights the growing importance of CELLETS® in pharmaceutical and scientific research. These microcrystalline cellulose spheres play a key role in developing reliable multiparticulate drug delivery systems. Researchers have investigated improved rivaroxaban dissolution, efficient film coating kinetics, and their use in orally disintegrating films. In addition, studies focus on colon-targeted vitamin B₂ release and fluidized-bed coating performance. Moreover, academic theses explore uniform hot-melt coating techniques and detailed modeling of tablet disintegration. As a result, MCC pellets continue to prove their versatility across many dosage forms. Consequently, this expanding body of literature reinforces the value of CELLETS® in advancing modern drug delivery technologies.
Selected Scientific literature on MCC pellets
Please, find scientific literature on MCC pellets (CELLETS®), MCC spheres. This list is constantly updated and does not claim to be complete. If you are author, scientist or R&D specialist, please submit your present publication to us for improving the visibility.
Research article Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating European Journal of Pharmaceutics and Biopharmaceutics, Volume 124, March 2018, Pages 13-27
Dolores R. Serrano, David Walsh, Peter O’Connell, Naila A. Mugheirbi, Zelalem Ayenew Worku, Francisco Bolas-Fernandez, Carolina Galiana, Maria Auxiliadora Dea-Ayuela, Anne Marie Healy
Conference abstract Multiple-unit orodispersible mini-tablets International Journal of Pharmaceutics, Volume 511, Issue 2, 25 September 2016, Page 1128
Anna Kira Adam, Christian Zimmer, Stefan Rauscher, Jörg Breitkreutz
Research article Asymmetric distribution in twin screw granulation European Journal of Pharmaceutics and Biopharmaceutics, Volume 106, September 2016, Pages 50-58
Tim Chan Seem, Neil A. Rowson, Ian Gabbott, Marcelde Matas, Gavin K. Reynolds, AndyIngram
Research article Physical properties of pharmaceutical pellets Chemical Engineering Science, Volume 86, 4 February 2013, Pages 50-60
Rok Šibanc, Teja Kitak, Biljana Govedarica, StankoSrčič Rok Dreu
Research article Labscale fluidized bed granulator instrumented with non-invasive process monitoring devices Chemical Engineering Journal, Volume 164, Issues 2–3, 1 November 2010, Pages 268-274
Jari T. T. Leskinen, Matti-Antero H. Okkonen, Maunu M. Toiviainen, Sami Poutiainen, Mari Tenhunen, Pekka Teppola, Reijo Lappalainen, Jarkko Ketolainen, Kristiina Järvinen
Research article Granule size distribution of tablets Journal of Pharmaceutical Sciences, Volume 99, Issue 4, April 2010, Pages 2061-2069
Satu Virtanen, Osmo Antikainen, Heikki Räikkönen, Jouko Yliruusi
Research article New insights into segregation during tabletting International Journal of Pharmaceutics, Volume 397, Issues 1–2, 15 September 2010, Pages 19-26
S. Lakio, S. Siiriä, H. Räikkönen, S. Airaksinen, T. Närvänen, O. Antikainen, J.Yliruusi
Research article In vivo evaluation of the vaginal distribution and retention of a multi-particulate pellet formulation European Journal of Pharmaceutics and Biopharmaceutics, Volume 73, Issue 2, October 2009, Pages 280-284
Nele Poelvoorde, Hans Verstraelen, Rita Verhelst, Bart Saerens, Ellen De Backer, Guido Lopes dos Santos Santiago, Chris Vervaet, Mario Vaneechoutte, Fabienne De Boeck, Luc Van Borteld, Marleen Temmerman, Jean-Paul Remon
List – Publications with MCC spheres, 2008 and earlier
Research article Attrition strength of different coated agglomerates Chemical Engineering Science, Volume 63, Issue 5, March 2008, Pages 1361-1369
B. van Laarhoven, S.C.A. Wiers, S.H. Schaafsma, G.M.H. Meesters
https://cellets.com/wp-content/uploads/2021/03/books-2463779_1920-small.jpg601854Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2025-10-07 08:48:012025-11-10 16:26:03Scientific Literature on MCC Pellets: Insights into CELLETS®
Hot-melt coating materials improve efficiency and product quality in pharmaceutical and industrial manufacturing. They melt when heated and solidify quickly, forming strong, uniform coatings on various surfaces. As a result, manufacturers reduce production time, lower costs, and avoid using solvents. Furthermore, understanding wetting behavior and delamination is critical to optimize coating performance. For example, CELLETS® 1000 microcrystalline cellulose pellets serve as excellent starter cores, promoting uniform wetting and consistent coating thickness. Consequently, hot-melt coating materials have become a reliable solution for modern manufacturing needs.
Enhancing pharmaceutical and industrial applications by hot-melt coating materials
In the study titled Delamination and Wetting Behavior of Natural Hot-Melt Coating Materials, published in Powder Technology [1], the authors investigated the delamination and wetting behaviors of various natural materials.The research aimed to understand how these materials interact with substrates during the coating process, which is crucial for applications in the pharmaceutical industry.The study utilized laboratory coating experiments and micro-computed tomographic measurements to assess delamination frequency, and a drop shape analyzer to evaluate wetting behavior.Interestingly, the study found no correlation between delamination and wetting behavior, suggesting that other factors may influence delamination in hot-melt coatings.
Among the materials tested, CELLETS® 1000, a type of microcrystalline cellulose (MCC) pellet with a size range between 1000 and 1400 µm, was highlighted for its suitability in hot-melt coating applications.These spherical pellets are known for their chemical inertness, low friability, high sphericity, and smooth surface, making them ideal as starter cores for multiparticulate drug delivery systems.In the context of the study, CELLETS® 1000 demonstrated excellent wetting properties with contact angles ranging from 10° to 18°, which is favorable for uniform coating.However, the study did not find a direct correlation between wetting behavior and delamination, indicating that other factors may play a more significant role in delamination during hot-melt coating processes. Researchers assume that delamination may have resulted from the different thermal expansion coefficients of the carrier particle and the coating material [2]. A change in temperature may have led to thermal stresses and may have promoted spalling or delamination. Subsequent swelling of a hygroscopic carrier material due to moisture could also lead to structural
changes in the coating structure and might cause delamination.
Use of CELLETS® in hot-melt coating processes
The use of CELLETS® in hot-melt coating processes offers several advantages.Their uniform size distribution and smooth surface contribute to consistent coating thickness and quality.Additionally, the chemical inertness of CELLETS® ensures compatibility with a wide range of coating materials, reducing the risk of undesirable interactions.These characteristics make CELLETS® a reliable choice for developing controlled-release formulations and enteric coatings in pharmaceutical applications.
In summary, the study underscores the importance of understanding the delamination and wetting behaviors of natural hot-melt coating materials.While CELLETS® 1000 exhibited favorable wetting properties, the lack of correlation between wetting behavior and delamination suggests that other factors should be considered when selecting materials for hot-melt coating processes.Further research is needed to identify these factors and optimize coating processes for improved product performance.
[2] S. Ebnesajjad, A.H. Landrock, Introduction and adhesion theories, Adhesives Technology, Handbook, 38, Elsevier 2015, pp. 1–18; doi: 10.1016/B978-0-323-35595-7.00001-2.
Understanding Hot-Melt Coating Materials
Hot-melt coating materials are thermoplastic substances that bond effectively to substrates when melted. Their melting point, adhesion properties, and chemical compatibility directly influence coating uniformity and durability. Therefore, selecting the correct material is crucial for minimizing delamination and ensuring product quality. Additionally, their solvent-free nature makes them environmentally friendly and cost-efficient.
Optimizing Coating with CELLETS®
CELLETS® offer significant advantages as starter cores in hot-melt coating processes. Their spherical shape and smooth surface promote uniform wetting and consistent coating thickness. Furthermore, their chemical inertness ensures compatibility with diverse coating materials, reducing the risk of unwanted interactions. Consequently, these MCC spheres support reliable and high-quality coating outcomes in both pharmaceutical and industrial applications.
Gamma‑hydroxybutyrate (GHB) is an endogenous neurotransmitter also used pharmaceutically—usually as sodium oxybate—for treating narcolepsy and related disorders. It exerts its therapeutic effects by modulating GABA_B receptors and promoting slow-wave sleep, alleviating cataplexy, and reducing excessive daytime sleepiness. Despite its efficacy, current twice-nightly dosing regimens present challenges: dose‑dumping in the presence of alcohol, variable pharmacokinetics depending on food intake, and patient inconvenience. To address these issues, modern formulations—and especially the innovative use of CELLETS® —pursue once-nightly controlled release.
API Benefits and Patient Advantages
Administering gamma‑hydroxybutyrate compositions in a modified‑release format brings multiple patient-centric benefits. A single nightly dose minimizes repeated nighttime awakenings and improves adherence. These formulations exhibit lower peak concentrations (C_max) with sustained therapeutic exposure (AUC)—achieving similar or better efficacy while reducing adverse events such as dizziness or nausea. This consistency is especially meaningful when dosing less than two hours after eating, which often is more convenient for patients; the controlled formulations are more forgiving of fed-state PK variability and less prone to alcohol-induced dose-dumping.
Use of CELLETS® in methods of administering gamma-hydroxybutyrate compositions
CELLETS® — spherical microcores used in multiparticulate drug delivery—are central to these modern GHB formulations. The patent US 20250186377 A1 introduces coated cellet-based microparticles that incorporate immediate-release (IR) and modified-release (MR) segments within a single unit dose. The MR portion involves CELLETS® (e.g. CELLETS® 90, CELLETS® 100 or CELLETS® 127, and other MCC beads) coated with polymers carrying free carboxyl groups combined with hydrophobic materials (e.g., high melting point waxes), engineered to delay GHB release until intestinal transit. CELLETS® enable precise layering, efficient coating, and reproducible drug release profiles while resisting pH- and alcohol-triggered dose dumping.
This multiparticulate approach achieves desired PK: IR CELLETS® ensure rapid onset while MR CELLETS® sustain plasma GHB levels up to 8 hours. In contrast to IR liquid sodium oxybate, the coated cellet formulation shows dose‑proportional C_max and AUC across doses of 4.5 g, 7.5 g, and 9 g, with most AEs clustering near C_max but at overall milder intensity. Remarkably, cellet-based formulations maintain comparable therapeutic exposure even with postprandial dosing, offering flexibility not seen in immediate-release forms.
Key Findings
The inventive cellet-based GHB composition delivers both immediate and controlled drug release in one unit, offering dose‑proportional pharmacokinetics and sustained therapeutic levels for 8 hours, under single-nightly dosing. It improves safety by reducing peak‑induced adverse events, lowers risk of alcohol‑related dose-dumping, and allows dosing within two hours after meals. Studies show comparable efficacy to twice-nightly IR sodium oxybate on sleep quality and daytime alertness, with better convenience and adherence.
Conclusion & Outlook
The patented cellet‑based modified-release formulation of GHB marks a significant advancement in administering gamma‑hydroxybutyrate compositions. By incorporating coated CELLETS® that combine IR and MR elements, this approach mitigates common limitations—meal dependency, alcohol interactions, multiple nightly doses—while preserving therapeutic efficacy. For patients with narcolepsy or cataplexy, this translates into improved sleep continuity, reduced daytime symptoms, and enhanced quality of life.
Looking ahead, further clinical evaluation could extend the CELLETS® platform to other formulations of gamma‑hydroxybutyrate salts or co‑therapies (e.g., with sodium valproate), further broadening the therapeutic utility. This modular, multiparticulate delivery system could set a new standard for nightly dosing regimens where controlled pharmacokinetics and patient preferences align.
Patent Holder(s): Not explicitly indicated in the publicly listed data, but associated inventors likely affiliated with pharmaceutical firms focusing on CNS therapeutics (e.g., Jazz Pharmaceuticals or Flamel Ireland).
https://cellets.com/wp-content/uploads/2025/07/US20250186377A1-cellet‑based-modified‑release-gamma‑hydroxybutyrate-formulation-ChatGPT-Image-11.-Juli-2025-13_12_09.jpg15361024Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2025-07-11 10:34:072025-07-11 13:42:48Patent on methods of administering gamma-hydroxybutyrate compositions with divalproex sodium
Colon Delivery of Vitamin B2: A Novel Food-Grade Approach
Innovative Food-Grade Delivery Systems
This article, “In vitro validation of colon delivery of vitamin B2 through a food grade multi-unit particle system,” [1] presents a novel method for delivering active ingredients to the colon. Specifically, it focuses on riboflavin in a food-grade and environmentally friendly form. The system uses a double-layer coated multi-unit particle system (MUPS). The MUPS features a cellulose core, an alginate inner layer, and a shellac outer layer. This design protects the particles as they pass through the upper digestive tract.
Moreover, tests show that the system releases about 90% of riboflavin directly in the colon. This release promotes gut health by increasing beneficial short-chain fatty acids. In addition, this sustainable method responds to the growing demand for effective colon-targeted health products. It also complies with EU regulations that restrict microplastic use in consumable goods.
The MUPS containing riboflavin, branded as Humiome® B2 by DSM-Firmenich, uses cellulose pellets called CELLETS® as its core. During manufacturing, producers apply riboflavin and pectin as a binder onto the Cellets using a fluid bed layering method. Next, they coat the MUPS with layers of sodium alginate and harden them with calcium chloride. Finally, they add a shellac outer layer. This structure controls the release of riboflavin in the colon and provides an efficient, food-grade delivery system for active nutrients.
Furthermore, the study highlights the effectiveness of the shellac-alginate MUPS for targeted riboflavin delivery to the colon. Food-grade materials support environmental standards, making this approach sustainable. In vitro tests confirm that approximately 90% of riboflavin reaches the colonic region. The results also indicate potential health benefits, including microbiome modulation and increased short-chain fatty acid production. Looking ahead, clinical studies will examine how this delivery system affects the microbiome and overall host health. These findings support its use in functional foods, dietary supplements, and medical nutrition.
Abstract
Colon-targeted delivery of active ingredients is common in pharmaceutical products. However, such delivery systems are rare in functional foods, beverages, dietary supplements, and medical nutrition. Nevertheless, emerging evidence shows that nutrients delivered to the colon can benefit gut microbiota and overall host health. This trend increases the demand for sustainable, food-grade materials that are approved for regulatory use.
In this paper, we describe a double-layer coated multi-unit particle system (MUPS) with a diameter of approximately 730 microns. It consists of food-grade materials: shellac as the outer layer, alginate as the inner layer, cellulose as the core, and riboflavin as the active ingredient. We tested the MUPS for colonic delivery using three well-established in vitro digestion and fermentation models: USP Apparatus 3, TIM-1, and TIM-2. All models confirmed that the MUPS remained intact through simulated upper gastrointestinal conditions. Furthermore, approximately 90% of riboflavin was released under simulated ileal-colonic conditions.
The TIM-2 model also revealed effects on microbiome composition, showing increased production of short-chain fatty acids, including acetate and butyrate. These results provide a solid foundation for validating this vitamin-loaded food-grade MUPS in future human clinical trials. Additionally, following the European Commission’s recent decision to restrict intentionally added microplastics in products, the materials used in this formulation offer an environmentally friendly alternative to traditional methyl acrylate coatings.
Reference
[1] Steinert, R.E., Sybesma, W., Duss, R., Rehman, A., Watson, M., van den Ende, T.C., & Funda, E. (2024). In vitro validation of colon delivery of vitamin B2 through a food grade multi-unit particle system. Beneficial Microbes, 16(2), 253-269. doi:10.1163/18762891-bja00045
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Packaged modified release gamma-hydroxybutyrate formulations improve stability and simplify treatment. The patent WO2019123269A1, titled “Packaged modified release gamma-hydroxybutyrate formulations having improved stability,” introduces innovative formulations and packaging methods. These methods enhance both dissolution and chemical stability of gamma-hydroxybutyrate (GHB), a therapy for narcolepsy. Currently, treatments like XYREM® force patients to wake during the night for a second dose, which proves cumbersome. Therefore, this patent develops a once-nightly, modified-release GHB formulation. Moreover, advanced packaging controls relative humidity, ensuring long-term effectiveness and preventing chemical degradation of GHB into gamma-butyrolactone (GBL).
Key Innovations:
Modified Release Formulation: The patent combines immediate and modified release components, both containing GHB or a pharmaceutically acceptable salt. The modified release component controls GHB release over time. As a result, it provides sustained therapeutic effects throughout the night. Therefore, patients do not need a second dose. Consequently, this formulation improves convenience and supports adherence to treatment.
Stability Issues with GHB: GHB is highly hygroscopic and chemically unstable. Consequently, it degrades easily, especially in high-humidity environments. This degradation produces GBL, which reduces the drug’s effectiveness. Therefore, the patent develops a formulation with stable dissolution profiles and improved chemical stability. Moreover, it maintains stability even under stressful storage conditions, such as high temperature and humidity.
Packaging Innovation: To enhance stability, the GHB formulations use packaging that maintains a specific relative humidity range (29% to 54%). This control of humidity is crucial because it prevents GHB from degrading into GBL. Moreover, the packaging material has a low water vapor transmission rate. As a result, it reduces moisture exposure and ensures the drug stays stable over time.
Hydrophobic Coating: The patent applies a hydrophobic coating, such as glyceryl tristearate or hydrogenated vegetable oil, along with methacrylic acid copolymers. These coatings control the release rate of GHB. Moreover, they protect it from moisture. As a result, the formulation provides a steady release and prevents premature degradation.
Pharmaceutical Composition: The GHB composition includes varying ratios of immediate and modified release components. These ratios ensure a sufficient therapeutic dose while maintaining stability. Moreover, particle size and formulation ratios (e.g., 40/60 to 60/40) play key roles in achieving the desired pharmacokinetics and release profiles.
Controlling the relative humidity within the packaging
The primary innovation lies in controlling the relative humidity within the packaging, alongside a modified release formulation with hydrophobic coatings to maintain the drug’s chemical stability and effectiveness. These advancements make GHB therapy more convenient by eliminating the need for a second nightly dose and addressing the stability challenges that have plagued previous formulations.
In this patent, CELLETS® play a crucial role as inert cores used in the formulation of modified release or the active or salts thereof. These starter spheres serve as carriers for the active ingredient by providing a surface for multi-layer drug layering. Their primary function is to ensure uniform drug distribution and control the release profile of GHB. The benefits include enhancing dissolution stability, maintaining the integrity of the dosage form over time, and helping to modulate the release rate of the drug for once-nightly dosing convenience. For these aspects, MCC starter sphere types where employed: CELLETS® 90, CELLETS® 100, CELLETS® 127. Glatt ProCell™ technique is used for spraying molten API.
Document information
Document Type and Number: (“Packaged modified release gamma-hydroxybutyrate formulations having improved stability”).
Kind Code: A1
Inventors:
Hervé GUILLARD
Disclaimer
This text was partly generated by chatGPT engine version GPT‑4o, on Oct 21, 2024. Image was generated with Adobe Firefly.
This article “Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets and Intended Process and Product Control” was published on Pharmaceutics2024, 16(10), 1307; https://doi.org/10.3390/pharmaceutics16101307, under free licence on October 08, 2024 by Marcel Langner, Florian Priese, and Bertram Wolf. We performed modifications of the text for better readability.
Abstract
Background/Objectives: Coated drug pellets are widely used in hard gelatine capsules. In heterogeneous pellets, the drug is layered onto core pellets. Coatings often provide retarded release or enteric protection.
Methods: In this study, we correlated polymer coating thickness on drug pellets with drug release kinetics.
Results: We investigated whether the coating process can be stopped once the desired layer thickness is achieved. First, inert pellets were coated with sodium benzoate. Then, they received different amounts of water-insoluble polyacrylate in a fluidized bed apparatus with a Wurster inlet. We controlled the entire process in-line and at-line using process analytical technology. This involved measuring particle size and layer thickness. Next, we examined in-vitro sodium benzoate release. We linearized the data with various standard models and compared it with polyacrylate layer thickness. As polyacrylate layer thickness increased, the release rate decreased. Several factors influenced release simultaneously, resulting in profiles that approximated first-order kinetics. Thus, the coating thickness corresponded to a specific drug release profile.
Conclusions: Manufacturing coated drug pellets with a targeted release is achievable through process control and layer thickness measurement. However, preliminary investigations are needed for each formulation.
1. Introduction
The dissolution of solid drug formulations depends on the solubility and dissolution rate of the drug substances. In addition, several factors influence release kinetics. For example, drug interaction with excipients, compression force and hardness in tablets, and the type of binder in granulates, pellets, or polymer coatings all play a role.
Understanding the dissolution rate and release kinetics is essential for optimal pharmacotherapy. Dissolution of solid substances typically follows first-order kinetics due to diffusion processes. However, some formulations show zero-order release, where equal amounts are released in equal time intervals.
Multiple processes often occur simultaneously. These include wetting of the dosage form, drug dissolution, diffusion of drug molecules out of the dosage form, swelling of matrix formulations, and water uptake by insoluble films. As a result, the kinetics may not fit simple zero-, first-, square-, or cubic-root order equations.
To evaluate the best approach, release data are linearized using various models. The coefficient of determination (CoD) of the linearized curve indicates the best fit and suggests which process likely dominates [1,2,3,4,5,6].
The model-independent parameters, difference factor f1 and similarity factor f2, are used to compare release profiles. f1 describes the relative error between two release profiles. It is calculated from the cumulative amounts released at a specific time T for a test and a reference formulation, or more generally, between any two formulations—for example, during drug development. On the other hand, f2 is based on the sum of squared deviations of the released drug amounts from the two profiles [4,5,7,8,9].
Focuses on drug-loaded pellets and their controlled release
Increasing attention has therefore focused on drug-loaded pellets and their controlled release. Specifically, this control is achieved by slowly swelling matrix systems or, alternatively, a final functional coating. Consequently, researchers have investigated the release of drugs from matrix pellets prepared by extrusion/spheronization and, moreover, coated with different amounts and types of insoluble ethylcellulose [10,11,12].
In addition, other studies report additional factors influencing drug release. For example, these include the filler type [13], the pH of the release fluid [4], storage conditions of the drug and methylcellulose matrix pellets [14], the amount of enteric polymer coating [15], and, finally, the salt concentration in the release fluid [16].
Further investigations examine the effects of talc and hydrogenated castor oil on the dissolution of metformin-loaded matrix pellets with an acrylic-based sustained-release coating [17]. Researchers also studied the sustained release of Lisinopril from mucoadhesive matrix pellets [18] and sinomenine hydrochloride from pellets produced using a novel whirlwind fluidized bed process [19].
Drug-layered inert pellets coated with polymer (heterogeneous pellets) were studied in order to assess the influence of release kinetics. Specifically, researchers investigated modifications of ethylcellulose coatings [20]; furthermore, they studied ethylcellulose mixed with polyvinylpyrrolidone (PVP) as a pore former [21], alternating layers of ethylcellulose and polyvinylacetate [22], various coating levels with final curing [23], and additionally, acetaminophen-layered sugar pellets coated with ethylcellulose [24]. Moreover, with polyacrylate coatings, drug release from layered pellets was delayed [7,25]. Therefore, changing the polymer type and layer thickness allowed control of the release rate over a wide range [8].
heterogeneous pellets coated with sodium benzoate
In our previous studies, heterogeneous pellets were manufactured using fluidized bed technology with a Wurster inlet. Initially, inert microcrystalline cellulose pellets (Cellets®175, median 170 µm), which offer a large specific surface area, were first coated with excipients as well as the water-soluble model drug sodium benzoate [26,27,28]. Consequently, these sodium benzoate (SB) pellets showed narrow particle size distribution, high sphericity, homogeneous layers, and additionally, rapid drug release. Subsequently, to achieve retarded release, the SB pellets were coated a second time with different amounts of ethylcellulose using the same fluidized bed technique [29]. As expected, the release rate decreased with increasing coating thickness. Moreover, the process was monitored in-line using spatial filter velocimetry (SFV) probes [27,28] to ensure control over particle size, distribution, and ethylcellulose layer thickness.
The present project aimed to produce heterogeneous pellets in a fluidized bed with a Wurster inlet while controlling the process using in-line particle size and coating thickness measurements. We studied sodium benzoate release kinetics, interpreted the partial processes affecting release, correlated release rate with polymer thickness, and determined the coating process endpoint to improve pellet quality.
PVP binder to improve layer stability
For pellet manufacturing, we followed a similar experimental approach to [26,27,28]. Small initial inert pellets (Cellets®175, median 170 µm) with large specific surface areas were coated with a sodium benzoate solution containing a small amount of PVP binder to improve layer stability. In the second step [29], SB pellets received varying amounts of insoluble but slowly swelling polyacrylate for retarded release. Agglomeration risk during coating was minimized by adjusting process parameters and adding talcum as an anti-stick agent. The SFV probe monitored particle size and detected agglomerates in real time.
Drug release was analyzed using zero-order, first-order, square-root, and cubic-root kinetic models. We identified the most likely release model by calculating area under the curve (AUC), dissolution efficiency (DE), and mean dissolution time (MDT), and by comparing the CoD of different models. We also calculated the difference factor f1 and similarity factor f2 to compare release profiles of different polyacrylate-layered pellet batches. Linearization works well for first-order kinetics. For other release profiles, nonlinear methods describe dissolution curves more accurately and reduce standard deviation in fitting parameters [30].
2. Materials and Methods
2.1. Materials
Pellets of microcrystalline cellulose (Cellets® 175, particle size range 150–200 µm, median 170 µm, IPC Dresden,, Germany), together with sodium benzoate (Applichem, Darmstadt, Germany, solubility 57 g in 100 g water at room temperature), PVP (Kollidon®25, Carl Roth, Karlsruhe, Germany), talcum (Talkum Pharma, C. H. Erbslöh, Krefeld, Germany), magnesium stearate (VEG Pharma, Rome, Italy), and additionally polyacrylate dispersion (Eudragit®NE 30D, Evonik Industries, Darmstadt, Germany, containing ethylacrylate-methylmethacrylate copolymer 30% w/w) were used. Importantly, all substances conform to European Pharmacopoeia (Ph.Eur.) quality [31].
2.2. Formulation of Sodium Benzoate-Coated Pellets
Microcrystalline cellulose pellets were coated with an aqueous solution of sodium benzoate 30% (w/w), PVP 1.5% (w/w) and talcum 0.5% (w/w) in a first coating step (Table 1). Sodium benzoate and PVP were dissolved one after another in purified water and finally talcum was suspended under agitation with a blade stirrer.
Table 1. Sodium benzoate pellet formulation.
Content (%)
Sodium benzoate
32.6
Microcrystalline cellulose
65.3
PVP
1.6
Talcum
0.5
100.0
2.3. Formulation of polyacrylate-coated sodium benzoate pellets
In the second coating step, SB pellets were layered with polyacrylate in three concentration lots: P1 (11.1% w/w PVP), P2 (14.3% w/w), and P3 (17.6% w/w). Magnesium stearate and talcum were added to the coating fluid. They acted as a plasticizer and an anti-stick agent, respectively (Table 2).
The polyacrylate coating fluid contained 13.3% (w/w) polyacrylate copolymer, 1.3% (w/w) magnesium stearate, and 5.3% (w/w) talcum. To prepare the mixture, we added a Eudragit®NE 30D dispersion to a beaker. Next, magnesium stearate and talcum were added one after another. The dispersion was homogenized under strong agitation with a disperser (Ultra Turrax T50 standard, Janke & Kunkel, IKA Labortechnik, Staufen, Germany; length 225 mm, diameter 18 mm, rotation 5000 rpm).
The coating process took place in a batch laboratory fluidized bed apparatus (GPCG 1.1, Glatt, Binzen, Germany). The system included a Wurster inlet and an SFV probe in the process chamber [27]. A spray nozzle of 1.0 mm diameter was used, with the nozzle cap set at 2.5 scales. The distance between the lower cylinder end and the perforated bottom plate B was fixed at 20 mm. The process air volume rate varied between 40 and 60 m³/h and was adapted to the increasing pellet weight during coating.
In the first step, Cellets®175 were coated with a sodium benzoate/PVP/talcum aqueous fluid (Table 3). In the second step, pellets received a polyacrylate dispersion under mild conditions. A lower spray rate and reduced process air temperature prevented pellet adhesion and sticking. Afterward, the polyacrylate-coated pellets were tempered for one hour at 30 °C. They were spread as a thin layer on a steel dish to allow coalescence and film formation.
Table 3. Process parameters of pellet fluidized bed coating with sodium benzoate (first step) and polyacrylate (second step).
Parameter
First Step
Second Step
sodium benzoate
polyacrylate
pellet batch (g)
300
process air temperature (°C)
80
40
product temperature (°C)
40
25
process air volume rate (m3/h)
40–60
spray rate (g/min)
20
6
spray pressure (bar)
3
2.5. Particle Size Coating Layer Thickness Measurement with SFV Probe
The particle size and thickness of the coating layer were measured in-line by the SFV probe (IPP 70, Parsum, Chemnitz, Germany). The probe was directly installed into the down-bed zone of the process chamber. Details of probe measurement are described elsewhere [27,28].
2.6. Sodium Benzoate Release and Content Investigation
The release was tested using a dissolution tester (PTW 2, Pharmatest, Hainburg). Specifically, the setup included six vessels containing 1.0 L purified water maintained at 37 °C, with a blade rotation of 75 rpm. Then, sampling took place at 10, 20, 30, 45, 60, 120, and 180 minutes. After each withdrawal, the volume was refilled with fresh purified water. Subsequently, sodium benzoate was analyzed using a UV–Vis spectrophotometer (Spekol 1300, Analytik Jena, Germany) with a 1 cm quartz cuvette at 220 nm.
For sodium benzoate content analysis, 50 mg of pellets were dispersed in 1.0 L purified water. These pellets contained 13.5 mg sodium benzoate. Dissolution and release were complete after 4 hours. The content was then analyzed as described above.
2.7. Linearization of Release Curves
The evaluation of the release curves was performed according to the different models of release kinetics also used by a number of authors [1,3,5,6,9,14]. In the first step of the release evaluation, the amount of cumulative released substance is plotted versus time. Linear curves arise in the case of zero order kinetics, i.e., equal amounts of the drug are released in equal time intervals (Equation (1)).
Mt = −k0 ∗ t + M0
First-order release kinetics are typical for slightly soluble drugs in solid preparations such as tablets, pellets, and granules. These systems are dominated by slow dissolution and diffusion control. At the beginning of the process, the release rate is highest. This occurs because the large concentration gradient drives diffusion, as described in Fick’s first law (Equation 2). However, the release rate gradually decreases as the concentration gradient diminishes during the process.
1/A ∗ dn/dt = −D ∗ dc/dx
The released amount Mt at the moment t refers to (Equation (3)), and linearization results in the Sigma minus function (Equation (4)).
Mt = M0 ∗ (1 − exp(−k1∗t))
ln (M0 − Mt) = ln (M0) − k1 ∗ t
The Weibull function (Equation (5)) and its linearized form (Equation (6)) presuppose first order kinetics.
Cubic root kinetics are observed in the case of spherical multiparticulate formulations (linearized form, Equation (8)).
Mt⅓ = M0⅓ − kc ∗ t
2.8. Model Independent Parameters: Difference Factor f1 and Similarity Factor f2
The difference factor f1 describes the relative error between two release profiles. It is calculated from the cumulative released amounts Ri and Ti at distinct time points for reference and test formulations (Equation 9). In contrast, the similarity factor f2 is based on the sum of squared deviations of released drug amounts (Equation 10). It expresses the statistical similarity between two profiles.
The f2 value equals 100 for identical profiles and ranges between 50 and 100 for similar ones. Together, both factors serve to compare the release profiles of generic and standard drug products. This comparison helps determine whether the generic profile matches or surpasses the standard.
In this study, we applied both factors to evaluate differences and similarities in sodium benzoate release profiles with various polymer coatings.
(9)
(10)
2.9. Microscopically Investigation
Coated pellets were placed on black paper for an improved contrast. Size and shape were investigated with a stereo light microscope (Stemi 2000-C, Carl Zeiss, Oberkochen, Germany, ocular: W-PI, 10×/23, magnification: 5.0, 50 scale = 1 mm). Photographs were shot by mobile.
2.10. Sphericity
The sphericity of the pellet lots was measured by digital image processing (Camsizer®, Retsch, Haan, measuring particle size range 40–3000 µm, measured particles 20,000 per second). The chord length was used for the evaluation of particle size and particle size distribution.
2.11. SFV Measurement
The SFV probe was installed directly into the process chamber of the fluidized bed apparatus between the inner chamber wall and the Wurster inlet. Details are described elsewhere [27].
3. Results and Discussion
3.1. Properties of Sodium Benzoate and Polyacrylate Coated Pellets
SB pellets are received as a free-flowing material. The coating process proceeded smoothly, and the Wurster inlet created a homogeneous fluidized bed pattern. As a result, the product shows a narrow particle size distribution [27]. The median x50.3 increased from 170 µm (uncoated Cellets® 175) to 200 µm. The sphericity of both the initial Cellets®175 and SB pellets remained above 0.9.
The polyacrylate coating of SB pellets caused no significant agglomeration. Only a few twins and triplets appeared under microscopic observation (Figure 1). The median size of polyacrylate-coated pellets grew to 232.2 µm, with a layer thickness of 16.1 µm (Table 4, P3, 17.6% polyacrylate content). Yield losses and incomplete sodium benzoate recovery resulted from material precipitation at the textile filter and inner chamber wall. Nevertheless, a sphericity above 0.9 confirms the formation of spherical products and indicates homogeneous processing.
Figure 1. SEM photograph of a polyacrylate coated SB pellet.
Table 4. Median, polyacylate layer thickness, product yield, sodium benzoate content and sphericity of polyacrylate coated SB pellets.
X50.3 (µm)
Polyacrylate
Layer
Thickness (µm)
Yield (%)
Sodium
Benzoate
Content (%)
Sphericity
(-)
P1
213.0
6.5
84
92
0.91
P2
221.0
10.5
P3
232.2
16.1
3.2. Sodium Benzoate Release Kinetics
3.2.1. Double Linear Diagram (Zero Order Release Kinetics)
After five minutes, more than 90% of sodium benzoate dissolves from SB pellets without a polymer layer. This is due to its high solubility and rapid dissolution rate. Sodium benzoate behaves as a strong electrolyte (sodium salt of benzoic acid, pKa 4.19 [31]), so it dissociates considerably into sodium cations and benzoate anions.
In contrast, the release from polyacrylate-coated pellets follows exponential curves (Figure 2). Generally, the release rate decreases as the polyacrylate layer thickens. The insoluble polyacrylate acts as a barrier. After ten minutes, 30% of sodium benzoate is released from low coating (P1), 20% from medium coating (P2), and 8% from high coating (P3).
diffusion of sodium benzoate molecules and ions
The dissolution rate of sodium benzoate alone cannot explain the release. Instead, diffusion of sodium benzoate molecules and ions through the polymer layer controls the rate. Initially, a high concentration gradient drives rapid release. Later, the release rate slows as the concentration gradient decreases.
For low coating (P1), the CoD of zero-order kinetics is 0.57 (Table 5), indicating zero-order release is unlikely. First-order diffusion seems to control the process. With increasing polyacrylate thickness, zero-order CoD rises (P2: 0.70, P3: 0.93). This reflects additional effects, such as polymer swelling and prolonged diffusion distance. Consequently, the release rate decreases as polyacrylate content rises, which is evident in decreasing AUC and DE, and increasing MDT (Table 6).
Figure 2. Double linear plot of the sodium benzoate release, SB pellets without polyacrylate layer, experimental release from polyacrylate-coated lots P1, P2 and P3 with increasing layer thickness and calculated release P1cal, P2cal and P3cal.
Table 5. CoD of sodium benzoate release profiles, kinetic models of zero order, first order, square root and cubic root; lots P1, P2 and P3.
CoD (R2)
Model
P1
P2
P3
Zero order
0.57
0.70
0.93
First order Sigma minus
0.98
0.98
0.95
First order Weibull
0.87
0.99
0.99
Square root
0.81
0.88
0.94
Cubic root
0.68
0.80
0.98
Table 6. Area under the curve, AUC, dissolution efficiency, DE, and mean dissolution time, MDT, of sodium benzoate release; lots P1, P2 and P3.
AUC (%∗min)
DE (-)
MDT (min)
P1
14,820
0.82
32
P2
13,927
0.77
41
P3
11,587
0.64
63
indicating equivalence between P1 and P2
The release profiles of lots P1 and P2 (Figure 2) differ only slightly. Therefore, the f1 value of 12 (Table 7) is below 15, indicating equivalence between P1 and P2. In contrast, the deviation between P1/P3 and P2/P3 is much more pronounced. This is due to the thicker polyacrylate coating layers, which lead to an f1 above 15. Consequently, these pairs are evaluated as “not equivalent” regarding the relative error between cumulative released amounts Ri and Ti at specific moments. Overall, increasing the coating layer thickness clearly changes the release profiles.
Table 7. Difference factor and similarity factor of sodium benzoate release profiles, comparison of lots P1, P2 and P3.
Parameter
Evaluation
P1/P2
P1/P3
P2/P3
Difference factor f1
“equivalent”
0–15
12
24
25
Similarity factor f2
“similar”
50–100
74
63
67
similarity factor f2 decreases with the increasing layer thickness
The similarity factor f2 decreases with the increasing layer thickness and diminished release rate, which is obvious comparing P1 with P2 (74) and P1 with P3 (63). Nevertheless, both f2s confirm the similarity of the release profiles.
Release curves (P1cal, P2cal and P3cal, Figure 2) were calculated according to first order kinetics (Equation (2)) and by use of the experimental release rate constants of P1, P2 and P3 (Table 5) from the Sigma minus plots (Figure 3).
Figure 3. First order Sigma minus function of the experimental and calculated (cal) sodium benzoate release, lots P1, P2 and P3.
The calculated double linear curves (grey) roughly matched the experimental curves (black, Figure 2). However, the deviation was greatest for P3, which had the thickest polyacrylate layer. This was caused by several coinciding processes: slow film wetting and swelling, delayed water uptake, and limited diffusion through the polyacrylate film to the sodium benzoate layer. Next came sodium benzoate dissolution and its diffusion through the swollen polymer into the release fluid.
The high coating thickness played a critical role. It created a long diffusion path and continuously altered the sodium benzoate concentration gradient within the polyacrylate layer. Consequently, these factors strongly influenced the overall release rate.
3.2.2. First Order Kinetics, Sigma Minus Function
The Sigma minus function gives linear trends of the sodium benzoate release (Figure 3) according to first order kinetics and a CoD above 0.9 (Table 5). The release rate constant k1 decreases with growing polyacrylate coating (Table 8). The calculated curves P1cal and P2cal (Equation (3)) meet the experimental curves of P1 and P2, respectively (Figure 3). The diffusion of sodium benzoate through the polyacrylate layer and to some extent the polymer swelling are the rate controlling steps. The more pronounced deviation of the experimental from the calculated curve in case of P3 is explained by the reasons mentioned above.
Table 8. First order release parameters of the Sigma minus and Weibull function, lots P1, P2 and P3.
k1 (1/min) Sigma Minus
b (-)
Weibull
1/a (-)
Weibull
t63.2% (min)
Weibull
P1
0.036
1.08
0.25
30
P2
0.030
1.58
0.17
40
P3
0.020
1.36
0.17
70
3.2.3. First Order Kinetics, Weibull Function
The Weibull function gives linear curves (Figure 4) comparable to the Sigma minus function (Figure 3) with coefficients of determination of 0.99 for P2 and P3 (higher polyacrylate coating) and a value of 0.87 for P1 (Table 5) due to the fast release in the initial phase and finally the slow release rate after 45 min (x-axis value 3.8, Figure 5).
Figure 4. First order Weibull function of the experimental sodium benzoate release, lots P1, P2 and P3.
Figure 5. Weibull function release parameter t63.2% versus coating layer thickness, lots P1 (coefficient of determination 0.87, polyacrylate content 6.5%), P2 (0.99, 10.5%) and P3 (0.99, 16.1%).
A shape parameter of 1 indicates monophasic release. In contrast, values above 1 suggest multiphasic release. In the present case, multiphasic release included an initial lag phase caused by wetting and swelling of the polyacrylate film. This was followed by an accelerated release rate up to the inflection point due to the high concentration gradient. Afterward, the rate slowed as the gradient decreased until drug dissolution and release were complete.
monophasic and multiphasic kinetics
P1, with low coating, showed nearly monophasic kinetics (shape parameter 1.08, Table 8). However, P2 (1.58) and P3 (1.36) indicated a more pronounced multiphasic release. The scale parameter (1/a) refers to the rate constant. It decreased with increasing coating thickness (Table 8). The time parameter t63.2% marks the moment when 63.2% of sodium benzoate is released. This value increased with higher polyacrylate thickness, ranging from 30 to 70 minutes (Table 8, Figure 5; see also Figure 2).
Clearly, polyacrylate coating thickness strongly influenced release kinetics (Table 4). A practical strategy for manufacturing coated pellets with controlled release is as follows. First, prepare laboratory-scale lots with increasing coating thickness. Then, measure thickness with the SFV probe. Next, investigate in vitro release and correlate it with polymer thickness. Finally, in production scale, stop the coating process once the desired thickness is detected.
3.2.4. Square Root Function
A cumulative release plot versus the square root of time yields straight lines for diffusion-controlled release. This is typical for non-disintegrating matrices such as tablets and semisolid systems (ointments, creams). Lots P1 and P2 showed nearly straight lines between 10 and 60 minutes (Figure 6). However, the initial phase (up to 10 minutes) and the terminal phase (after 60 minutes) did not fit the square root model. The CoD values ranged from 0.81 for P1 to 0.94 for P3 (Table 5). Therefore, the square root model was not suitable to describe the release from pellets with an insoluble but swellable polymer coating.
Figure 6. Square root function of the experimental sodium benzoate release, lots P1, P2 and P3.
3.2.5. Cubic Root Function
The cubic root function applies to the dissolution of spherical particles. This is because both weight and surface area decrease during dissolution. When the cubic roots of the dose and cumulative released substance are plotted against time, straight lines should appear.
However, this was not observed for sodium benzoate release from polyacrylate-coated pellets (Figure 7). The deviation from linearity was clear in lots P1 and P2, especially in the terminal release phase after 45 minutes. Their CoD values were 0.68 and 0.80, respectively (Table 5). In contrast, the slower-releasing P3 showed a nearly straight curve with a CoD of 0.98.
Thus, the cubic root model seems suitable only for pellets with thick polyacrylate coatings. Lots P1 and P2, with thinner coatings, did not follow cubic root kinetics or typical sphere dissolution.
Figure 7. Cubic root function of the experimental sodium benzoate release, lots P1, P2, and P3.
4. Conclusions
Inert Cellets® 175 were coated in two steps. First, they received the model drug sodium benzoate. Second, they were coated with a water-insoluble polyacrylate dispersion in a fluidized bed with a Wurster inlet. Particle size increase and coating thickness were measured in-line during the entire process using the SFV probe. Sodium benzoate release was then tested in vitro. The release profiles were linearized and evaluated with different kinetic models.
As the polyacrylate coating layer thickened, the sodium benzoate release rate decreased. This trend was confirmed by release parameters, rate constants, AUC, MDT, and DE. A difference factor f1 above 15 indicated dissimilar profiles between low-coated (P1, P2) and high-coated (P3) pellets. Thus, coating thickness significantly influenced sodium benzoate release. The similarity factor f2 ranged from 67 to 74, confirming comparable release profiles across lots P1, P2, and P3.
high CoD values
The high CoD values of linearized release profiles suggested first-order kinetics as the most suitable model. This outcome can be explained by the strong effect of sodium benzoate diffusion through the swollen polyacrylate film. With thicker coatings, polymer swelling increased. Consequently, diffusion distances for water and sodium benzoate grew longer, while concentration gradients exerted stronger control over release.
Overall, the detailed study of release profiles in relation to coating thickness allows accurate detection of the coating endpoint. Therefore, the method supports manufacturing custom-coated drug pellets with defined release properties.
Authors and affiliations
Marcel Langner (1), Florian Priese (2), and Bertram Wolf (2)
1 IDT Biologika, Am Pharmapark, 06861 Dessau-Roßlau, Germany
2 Department of Applied Biosciences and Process Engineering, Anhalt University of Applied Sciences, Bernburger Straße 55, 06366 Köthen, Germany
Author Contributions
Conceptualization, B.W.; methodology, M.L.; data curation, B.W.; writing—original draft preparation, M.L.; writing—review and editing, F.P. and B.W.; supervision, F.P.; project administration, B.W.; funding acquisition, F.P. All authors have read and agreed to the published version of the manuscript.
Funding
This work was financially supported by the Federal Ministry of Education and Research of Germany (BMBF) within the research project WIGRATEC+ and the German Research Foundation (Deutsche Forschungsgemeinschaft DFG)—project number 491460386—plus the Open Access Publishing Fund of Anhalt University of Applied Sciences.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
All relevant data are available in the article.
Conflicts of Interest
The authors declare no conflicts of interest.
Notations
M0
initial drug dose, drug content
(%)
Mt
released drug amount at time
(%)
AUC
area under the curve
(%*min)
DE
dissolution efficiency
(-)
MDT
mean dissolution time
(min)
Ti
released drug amount at moment t test formulation
(%)
Ri
released drug amount at moment t reference formulation
(%)
n
number of time points
(-)
I
release time point
(min)
T
moment of drug release
(min)
k0
release rate constant, zero order release kinetics
(%/min)
k1
release rate constant, first order release kinetics
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https://cellets.com/wp-content/uploads/2024/10/Firefly-create-a-cover-image-for-the-scientific-article-nfluence-of-Polymer-Film-Thickness-on-Drug-.jpg20482048Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2024-10-16 17:24:312025-08-20 16:18:44Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets and Intended Process and Product Control
The focus of the current work is to study and demonstrate the impact of the design, the scale, and settings of fluid-bed coating equipment on the differences in pellet coating thickness, which in case of prolonged-release pellets dictates the drug release. In the first set of coating experiments, the pellet cores were coated with the Tartrazine dye with the aim of estimating the coating equipment performance in terms of coating thickness distribution, assessed through color hue. In the second set, drug-layered pellets were film-coated with prolonged-release coating and dissolution profile tests were performed to estimate the thickness and uniformity of the coating thickness among differently sized pellets. In both study parts, film coating was performed at the laboratory and the pilot scale and essentially two types of distribution plate and different height adjustments of the draft tube were compared. The dye coating study proved to be extremely useful, as the results enable process correction and the optimal use of the process equipment in combination with the appropriate process parameters. Preferential film coating of larger drug-containing pellets was confirmed on the laboratory scale, while on the pilot scale, it was possible to achieve preferential coating of smaller pellets using rational alternatives of settings, which is desirable in terms of particle size-independent drug release profile of such prolonged-release dosage forms. […]
Materials
In the first part of the study, neutral MCC pellets (CELLETS 700, IPC Process Center GmbH, Germany) were coated with water solution composed of 8% w/w HPMC 6 mPas (Shin-Etsu Chemical, Japan), 1% w/w Macrogol 6000 (Clariant Produkte GmbH, Glendorf site, Germany), 1% w/w coloring agent Tartrazine (Sigma-Aldrich, USA), and purified water (90%, w/w).
In the second part of coating experiments, API-coated pellets containing Diclofenac sodium were coated with water-based sustained release coating dispersion containing Eudragit RS 30D (9.6% w/w), Eudragit RL 30 D (19.2% w/w) (Evonic Nutrition Care GmbH, Germany), 1.7% w/w triethyl citrate (Vertellus LLC, USA), and 10.4% w/w talc.
Methods
Pellet Film-Coating Experiments with Tartrazin
Coating experiments using Tartrazine dye were performed on two laboratory-sized fluid-bed coaters (GPCG1, Glatt GmbH, Germany and BX FBD10, Brinox d.o.o., Slovenia) and on one pilot-sized (BX FBD30, Brinox d.o.o., Slovenia) fluid-bed coater. In case of both laboratory coaters, the type of distribution plate and the gap between the plate and the draft tube were varied. The pilot-scale setup with three swirl generators and draft tubes was used, while only the size of the gap was varied during coating experiments (Table I). All other process parameters were comparable within each coating process scale. […]
Size distributions of uncoated CELLETS® 700 used in Tartrazine coating experiments and of drug-layered pellets used in PR coating experiments
Conclusion
Considering the results of the coating process evaluation with the dye-coated pellet approach, based on previous research, it can be said that the obtained positive slopes of size preferential coating in the laboratory-scale CW process chamber are within the expected performance of this type of coater design. The values of the slope of the size preferential coating were always lower in the case of the SW distribution plate in comparison with the CW design of the distribution plate. However, within the laboratory-scale coater designs, different performances of swirl generator equipped flat and funnel-shaped distribution plates were identified, the latter exhibiting the least size dependent preferential coating performance. This was attributed to a less expressed dead zone effect enabling mixing and elimination of any segregation in the pellet bed region of the coater. On the pilot film-coating scale, coater equipped with flat SW distribution plates exhibited negative size preferential coating slope, meaning that smaller pellets obtained more coating than larger ones, which is unprecedented result. Moreover, the extent of the negative size preferential coating slope depended on the dynamics of the pressure drop fluctuations. This finding was effectively translated to the prolonged-release coating application, where the right extent of the negative size preferential coating ensures pellet size-independent drug release profiles, thus improving robustness of such multiple unit prolonged-release formulation. By lowering the air flow rate and using bimodal size distribution, rich in smaller drug-layered pellets, led to rather surprising results, where performance of prolonged drug release-coated pellets did not resemble size preferential coating results from the dye coating study part.
These results confirm the fact that we must have a good knowledge of the coater performance characteristics in combination with the process variables and even formulation properties, if we want to produce coated multiple-unit solid pharmaceutical products of the highest quality.
https://cellets.com/wp-content/uploads/2023/04/Titelbild-Brezovar-2023.jpg6271200Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2024-04-26 17:17:462024-04-26 17:17:46The Effect of Design and Size of the Fluid-Bed Equipment on the Particle Size-Dependent Trend of Particle Coating Thickness and Drug Prolonged-Release Profile
Using cocrystals has emerged as a promising strategy to improve the physicochemical properties of active pharmaceutical ingredients (APIs) by forming a new crystalline phase from two or more components. Particle size and morphology control are key quality attributes for cocrystal medicinal products. The needle-shaped morphology is often considered high-risk and complex in the manufacture of solid dosage forms. Cocrystal particle engineering requires advanced methodologies to ensure high-purity cocrystals with improved solubility and bioavailability and with optimal crystal habit for industrial manufacturing. In this study, 3D-printed microfluidic chips were used to control the cocrystal habit and polymorphism of the sulfadimidine (SDM): 4-aminosalicylic acid (4ASA) cocrystal. The addition of PVP in the aqueous phase during mixing resulted in a high-purity cocrystal (with no traces of the individual components), while it also inhibited the growth of needle-shaped crystals. When mixtures were prepared at the macroscale, PVP was not able to control the crystal habit and impurities of individual mixture components remained, indicating that the microfluidic device allowed for a more homogenous and rapid mixing process controlled by the flow rate and the high surface-to-volume ratios of the microchannels. Continuous manufacturing of SDM:4ASA cocrystals coated on beads was successfully implemented when the microfluidic chip was connected in line to a fluidized bed, allowing cocrystal formulation generation by mixing, coating, and drying in a single step.
Conclusions
SDM:4ASA cocrystal particle engineering has been successfully achieved using 3D-printed microfluidic chips. The addition of PVP in the aqueous phase during mixing has allowed the inhibition of needle-shaped crystals and the generation instead of spherical crystal habits with higher purity compared to conventional mixing. A successful continuous manufacturing method for the fabrication of cocrystal-coated particles has been demonstrated by the combination of microfluidic chips with a fluidized bed, allowing the process intensification of mixing and drying in one step.
Authors:
Aytug Kara, Dinesh Kumar, Anne Marie Healy, Aikaterini Lalatsa, and Dolores R. Serrano.
Read more
Read more on continuous manufacturing of cocrystals by Kara et al. here and find out the functionality of CELLETS® 500 (pellets made of microcrystalline cellulose, size: 500-710 µm).
The primary objective of this research is to investigate the design and size on particle coating thickness. Furthermore, illustrate how the design, size, and configurations of fluid-bed coating machinery influence variations in pellet coating thickness. This parameter plays a crucial role in governing the release of medication in prolonged-release pellets. Initially, the scientists conducted a series of coating experiments where the pellet cores were coated with Tartrazine dye. The aim was to evaluate the performance of the coating equipment in terms of the distribution of coating thickness, which was assessed based on color hue.
In the subsequent set of experiments, drug-layered pellets underwent film-coating with prolonged-release material. Brezovar et al. conducted dissolution profile tests to gauge the uniformity and thickness of the coating among pellets of different sizes. Pellets of kind CELLETS® 700 (IPC Dresden, Germany) had been employed. This investigation encompassed both laboratory and pilot scale applications. Laboratory-sized fluid-bed coaters GPCG1 (Glatt GmbH, Germany and BX FBD10, Brinox d.o.o., Slovenia) and a pilot-sized (BX FBD30, Brinox d.o.o., Slovenia) fluid-bed coater are used for these tests. The group made comparisons between two types of distribution plates and various adjustments in the height of the draft tube.
The dye coating study yielded highly valuable insights. The results provided the basis for refining the process and optimizing the utilization of process equipment, especially in conjunction with the appropriate process parameters. On the laboratory scale, we observed a preference for film coating larger drug-containing pellets. However, on the pilot scale, we achieved a preferential coating of smaller pellets through judicious adjustments, a development that holds significance in achieving a drug release profile independent of particle size for prolonged-release dosage forms.
https://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.png00Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2023-09-19 16:52:222023-09-19 16:52:56Investigating the Influence of Fluid-Bed Equipment Design and Size on Particle Coating Thickness Trends and Drug Prolonged-Release Profiles Linked to Particle Size
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